P726: TET2 ALLELIC BURDEN IMPRINTS A CONTEXT-DEPENDENT PROGNOSTIC SIGNIFICANCE OF ASXL1 MUTATION IN CHRONIC MYELOMONOCYTIC LEUKAEMIA
Authors: Yu-Hung Wang, Carmelo Gurnari, Hussein Awada, Kristian Gurashi, Kiran Batta, Jaroslaw P. Maciejewski, Daniel H. Wiseman
Journal: HemaSphere (2023)

Background: Chronic myelomonocytic leukaemia (CMML) is a clonal myeloid neoplasm characterised by malignant monocytosis and myeloid dysplasia, dominated by somatic mutations in epigenetic, splicing and signalling genes. While ASXL1 mutations have been associated with poor prognosis in CMML, TET2 mutations seem to imprint a relative survival advantage, especially amongst ASXL1-wild type patients. Since ASXL1 and TET2 are among the most common mutations in CMML, we investigated whether the prognostic impact of mutated ASXL1 can be partially mitigated by concurrent TET2 mutation, with incorporation of its allele burden for outcome prognostication. Aims: This study aims to investigate the clinical relevance of TET2 variant allele fraction (VAF) in CMML patients harboring different ASXL1/TET2 compound genotypes, to improve risk-stratification. Methods: We retrospectively analysed data for 137 CMML patients treated at the Christie Hospital (2006-2021), for whom biobanked genomic DNA was available, and adopted TruSight myeloid sequencing panel and HiSeq platform to analyse the gene alterations. A cohort of 89 CMML patients from the Cleveland Clinic was enrolled for validation. Results: Overall, the median age of the 137 CMML patients was 75 years. Ninety-nine patients (72.2%) had CMML-1, and 45.3% proliferative-type CMML. TET2 was the most frequently mutated gene (66%), followed by SRSF2 (46%) and ASXL1 mutations (45%), as expected. Overall, 140 TET2 mutations were identified in 90 patients and 47 (52%) patients carried multiple TET2 mutations. Median TET2 VAF was 43.5% (range, 4–96.4%) for all TET2 mutations. Patients were divided into high vs low TET2 VAF with median as a cut-off. TET2highVAFpatients were more likely to have proliferative-CMML (p=0.086) and higher absolute neutrophil count (p=0.073). No significant difference regarding other clinical features, disease risks and genomic makeup was found. Median overall survival (OS) of the entire cohort was 36 months and was well stratified by CMML-specific prognostic scoring, CPSS-Molecular risk, and the Mayo Prognostic Model status (respective p, <0.001, 0.002, and 0.001). TET2-mutated patients had better leukaemia-free survival (LFS) and OS than TET-wild type patients. Moreover, concurring with recent studies, patients with ≥2 TET2 mutations had a superior OS comparing to both TET2-single mutant (p=0.001) and TET2-unmutated patients (p=0.002). OS was comparable between the TET2highVAF vs TET2lowVAF patients (p=0.65). However, analysis integrating ASXL1 mutation status and TET2 VAF revealed that ASXL1 mutations conferred poorer OS in TET2highVAF patients (median, 27.6 vs 98.9 months, p=0.002) but not in TET2lowVAF patients (median, 40.6 vs 46.9 months, p=0.683) (Figure 1). This finding was reproducible in the external validation cohort (TET2highVAF and TET2lowVAF groups, p=0.041 and p=0.344, respectively). Time-dependent ROC curve analyses showed that integrating TET2 VAF with ASXL1 mutation could be complementary to current risk stratification systems in predicting LFS/OS of CMML patients. Finally, ASXL1/TET2highVAF was identified as an independent adverse prognostic factor by multivariable analysis, irrespective of age, risk stratification systems, and other mutations (SETBP1, NRAS, RUNX1). Conclusion: We observe that the compound genotype of ASXL1 mutation accompanied by a high mutant TET2 allele burden identified a distinct CMML population with significantly reduced survival, with independent prognostic relevance extrapolated to and validated in an independent cohort. Prospective and large-scale studies are warranted to support these observations and experimental studies are needed to ascertain the underlying mechanistic basis. Figure 1Keywords: TET2, Chronic myelomonocytic leukemia, ASXL1, Prognosis